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Science 25 March 2005:
Vol. 307. no. 5717, pp. 1904 - 1909
DOI: 10.1126/science.1104815
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Review

Self-Renewal and Cancer of the Gut: Two Sides of a Coin

Freddy Radtke1 and Hans Clevers2*

The intestinal epithelium follows the paradigms of stem cell biology established for other self-renewing tissues. With a unique topology, it constitutes a two-dimensional structure folded into valleys and hills: the proliferative crypts and the differentiated villi. Its unprecedented self-renewal rate appears reflected in a high susceptibility to malignant transformation. The molecular mechanisms that control homeostatic self-renewal and those that underlie colorectal cancer are remarkably symmetrical. Here, we discuss the biology of the intestinal epithelium, emphasizing the roles played by Wnt, bone morphogenic protein, and Notch signaling cascades in epithelial self-renewal and cancer.

1 Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Chemin de Boveresses 155, CH-1066 Epalinges, Switzerland.
2 Hubrecht Institute, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT Utrecht, Netherlands.

* To whom correspondence should be addressed. E-mail: clevers{at}niob.knaw.nl

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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V. Muncan, O. J. Sansom, L. Tertoolen, T. J. Phesse, H. Begthel, E. Sancho, A. M. Cole, A. Gregorieff, I. M. de Alboran, H. Clevers, et al. (2006)
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   Abstract »    Full Text »    PDF »
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M. Y. Choi, A. I. Romer, M. Hu, M. Lepourcelet, A. Mechoor, A. Yesilaltay, M. Krieger, P. A. Gray, and R. A. Shivdasani (2006)
Development 133, 4119-4129
   Abstract »    Full Text »    PDF »
Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin.
P. Ma, S. L. Beck, R. W. Raab, R. L. McKown, G. L. Coffman, A. Utani, W. J. Chirico, A. C. Rapraeger, and G. W. Laurie (2006)
J. Cell Biol. 174, 1097-1106
   Abstract »    Full Text »    PDF »
Dual roles for adenomatous polyposis coli in regulating retinoic acid biosynthesis and Wnt during ocular development.
L. D. Nadauld, S. Chidester, D. N. Shelton, K. Rai, T. Broadbent, I. T. Sandoval, P. W. Peterson, E. J. Manos, C. M. Ireland, H. J. Yost, et al. (2006)
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   Abstract »    Full Text »    PDF »
Protein tyrosine kinase 6 negatively regulates growth and promotes enterocyte differentiation in the small intestine..
A. Haegebarth, W. Bie, R. Yang, S. E. Crawford, V. Vasioukhin, E. Fuchs, and A. L. Tyner (2006)
Mol. Cell. Biol. 26, 4949-4957
   Abstract »    Full Text »    PDF »
Repression of Prostaglandin Dehydrogenase by Epidermal Growth Factor and Snail Increases Prostaglandin E2 and Promotes Cancer Progression..
J. R. Mann, M. G. Backlund, F. G. Buchanan, T. Daikoku, V. R. Holla, D. W. Rosenberg, S. K. Dey, and R. N. DuBois (2006)
Cancer Res. 66, 6649-6656
   Abstract »    Full Text »    PDF »
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K. Willert and K. A. Jones (2006)
Genes & Dev. 20, 1394-1404
   Abstract »    Full Text »    PDF »
Normal Stem Cells and Cancer Stem Cells: The Niche Matters..
L. Li and W. B. Neaves (2006)
Cancer Res. 66, 4553-4557
   Abstract »    Full Text »    PDF »
Molecular Properties of Adult Mouse Gastric and Intestinal Epithelial Progenitors in Their Niches.
M. Giannakis, T. S. Stappenbeck, J. C. Mills, D. G. Leip, M. Lovett, S. W. Clifton, J. E. Ippolito, J. I. Glasscock, M. Arumugam, M. R. Brent, et al. (2006)
J. Biol. Chem. 281, 11292-11300
   Abstract »    Full Text »    PDF »
Stem cells and their niches..
K. A. Moore and I. R. Lemischka (2006)
Science 311, 1880-1885
   Abstract »    Full Text »    PDF »
The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes..
J. Sierra, T. Yoshida, C. A. Joazeiro, and K. A. Jones (2006)
Genes & Dev. 20, 586-600
   Abstract »    Full Text »    PDF »
Identification of the IFITM Family as a New Molecular Marker in Human Colorectal Tumors.
P. Andreu, S. Colnot, C. Godard, P. Laurent-Puig, D. Lamarque, A. Kahn, C. Perret, and B. Romagnolo (2006)
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   Abstract »    Full Text »    PDF »
Appendage Regeneration in Adult Vertebrates and Implications for Regenerative Medicine.
J. P. Brockes and A. Kumar (2005)
Science 310, 1919-1923
   Abstract »    Full Text »    PDF »
{beta}-Catenin is essential for pancreatic acinar but not islet development.
L. C. Murtaugh, A. C. Law, Y. Dor, and D. A. Melton (2005)
Development 132, 4663-4674
   Abstract »    Full Text »    PDF »
On mammary stem cells.
W. A. Woodward, M. S. Chen, F. Behbod, and J. M. Rosen (2005)
J. Cell Sci. 118, 3585-3594
   Abstract »    Full Text »    PDF »
Notch signaling regulates the differentiation of post-mitotic intestinal epithelial cells.
V. Zecchini, R. Domaschenz, D. Winton, and P. Jones (2005)
Genes & Dev. 19, 1686-1691
   Abstract »    Full Text »    PDF »
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D. Y. R. Stainier (2005)
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   Abstract »    Full Text »    PDF »


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